Epidemiologic studies demonstrate that the relative risk of AD is lower in subjects with a history of NSAID use. These clinical data together with the presence of inflammatory markers in the AD brain has prompted investigation into the role that inflammation plays in AD pathology as well as further study of the potential efficacy of anti- inflammatory drugs in AD. We have recently found that some, but not all, NSAIDs selectively decrease Abeta42 production both in cultured cells and acutely in the brain of APP transgenic animals by a mechanism that is independent of cyclooxygenase (Cox) inhibition. Moreover, an independent study showed that chronic treatment with ibuprofen reduced Abeta deposition in a transgenic mouse model (2). Together, these data suggest that certain NSAIDs selectively reduce Abeta42, and that this effect rather than the classical, COX mediated, anti-inflammatory properties of these compounds might account for their apparent efficacy both in reducing risk for AD and reducing Abeta deposition in APP transgenic mice. In this project, we propose to identify existing NSAIDs or structural analogs of NSAIDs that show increased potency and selectivity for the Abeta42 lowering effect relative to Cox inhibition using screens in cultured cells followed by acute studies of candidate compounds in APP transgenic mice. Novel compounds with this unique inhibitory profile along with FDA approved NSAIDs that either possess Abeta42 lowering ability (e.g., ibuprofen, meclofenamic acid, sulindac) or lack Abeta42 lowering activity (e.g., naproxen, celecoxib, NS-398) will then be tested for their effects on Abeta deposition, other AD-like pathology and behavioral changes in long-term therapeutic and preventative studies in the Tg2576 mouse model of AD. These long-term animal model studies should provide information on the properties of these compounds that are most closely related to a reduction in amyloid deposition and AD pathology, and may lead to the identification of novel compounds that could prove efficacious for the treatment or prevention of AD.